tbuckley/cabot-search huggingface dataset:
Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation
Authors: Lin Zhu, Xinwei Kuang, Guanxiong Zhang, Long Liang, Dandan Liu, Bin Hu, Zuozhong Xie, Hui Li, Hong Liu, Mao Ye, Xiang Chen, Jing Liu
Journal: Journal for ImmunoTherapy of Cancer (2022)

Immune checkpoint inhibitors (ICIs) have been increasingly used in patients with various cancers and have shown efficient therapeutic outcomes. However, fewer than 40% of cases across multiple cancer types show a response to ICIs. Therefore, developing more efficient combinational approaches with ICIs and revealing the underlying mechanisms are important goals for achieving rapid clinical transformation and application.The effects on antitumor immunity activity of albendazole (ABZ) and the synergistic effects of ABZ with CD73 blockade were investigated in the melanoma B16F10 and the Lewis lung cancer tumor-bearing immune-competent mice models. The mechanism of ABZ reducing PD-L1 protein level through suppressing UBQLN4 was identified and validated through immunoprecipitation-mass spectrometry and molecular methods. Bioinformatics and anti-PD-1 therapy melanoma patients samples analysis were used to assess the level of UBQLN4/PD-L1 in the therapeutic efficacy of anti-PD-1 therapy.ABZ induces CD8+ T cell activity and subsequent immunotherapy response associated with suppression of PD-L1 protein level. Mechanistically, we revealed that ABZ promotes ubiquitin-mediated degradation of PD-L1 via suppressing UBQLN4, which was bound to PD-L1 and stabilized PD-L1 protein. Preclinically, genetic deletion or target inhibition of CD73 showed synergistic effects with ABZ treatment in the immune-competent mice models. Significantly, UBQLN4 and PD-L1 levels were higher in the tumor region of responders versus non-responders and correlated with better progression-free survival and overall survival in anti-PD-1 therapy melanoma patients.Our findings revealed a previously unappreciated role of ABZ in antitumor immunity by inducing ubiquitin-mediated PD-L1 protein degradation, identified predictors for assessing the therapeutic efficacy of anti-PD-1 therapy, and provided novel therapeutic possibility by combination treatment of ABZ and CD73 blockade in cancers.
LncRNAs and CircRNAs in cancer
Authors: Xin Yin, Huiran Lin, Lei Lin, Lei Miao, Jing He, Zhenjian Zhuo
Journal: MedComm (2022)

Abstract It is well known that noncoding RNAs (ncRNAs) cannot encode proteins, but they can play important regulatory roles in tumors by combining with proteins, RNAs, and DNAs. As more and more studies reveal the important roles and underlying mechanisms of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in cancer, their huge application potential in cancer therapy cannot be ignored. For example, lncRNAs can be involved in tumor‐related signal transduction pathways, cell cycle control, DNA damage, epigenetic regulation, and microRNA control. A group of studies confirmed that abnormal expression of lncRNAs can affect cancer progression. Furthermore, as covalently closed continuous circular ncRNAs, many recent studies have shown that circRNAs have regulatory effects and other important biological significances in cancer. Interestingly, circRNAs were found to have translational functions. This has greatly attracted people's attention to circRNAs research. In this review, we introduce the important roles of lncRNAs and circRNAs in some representative cancers, respectively. Furthermore, we focus on the biological functions and important clinical therapeutic implications of lnRNAs and circRNAs in neuroblastoma. Our review also focuses on providing rationale and relevant references for novel biomarkers for neuroblastoma diagnosis, prognosis, and treatment.
Empagliflozin add-on therapy to closed-loop insulin delivery in type 1 diabetes: a 2 × 2 factorial randomized crossover trial
Authors: Ahmad Haidar, Leif Erik Lovblom, Nancy Cardinez, Nikita Gouchie-Provencher, Andrej Orszag, Michael A. Tsoukas, C. Marcelo Falappa, Adnan Jafar, Milad Ghanbari, Devrim Eldelekli, Joanna Rutkowski, Jean-François Yale, Bruce A. Perkins
Journal: Nature Medicine (2022)
Abstract B001: Developing adaptive therapy to suppress the evolution of treatment resistance in high-grade serous ovarian cancer
Authors: Helen Hockings, Michelle Lockley, Trevor Graham, Eszter Lakatos, Weini Huang
Journal: Cancer Research (2022)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR015) of the Conference Proceedings. Citation Format: Helen Hockings, Michelle Lockley, Trevor Graham, Eszter Lakatos, Weini Huang. Developing adaptive therapy to suppress the evolution of treatment resistance in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B001.
Criteria for the pathogenicity of anticentromere (anti–CENP‐B) autoantibodies in systemic sclerosis: comment on the article by van Leeuwen et al
Authors: Jean‐Luc Senécal, Martial Koenig, Gabriel Archambault, Sabrina Hoa
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Improving lithium dose prediction using population pharmacokinetics and pharmacogenomics: a cohort genome-wide association study in Sweden
Authors: Vincent Millischer, Granville J Matheson, Sarah E Bergen, Brandon J Coombes, Katja Ponzer, Fredrik Wikström, Karolina Jagiello, Martin Lundberg, Peter Stenvinkel, Joanna M Biernacka, Olof Breuer, Lina Martinsson, Mikael Landén, Lena Backlund, Catharina Lavebratt, Martin Schalling
Journal: The Lancet Psychiatry (2022)
Longitudinal Trajectory of the Link Between Ventral Striatum and Depression in Adolescence
Authors: Pedro Mario Pan, João R. Sato, Marie-Laure Paillère Martinot, Jean-Luc Martinot, Eric Artiges, Jani Penttilä, Yvonne Grimmer, Betteke M. van Noort, Andreas Becker, Tobias Banaschewski, Arun L. W. Bokde, Sylvane Desrivières, Herta Flor, Hugh Garavan, Bernd Ittermann, Frauke Nees, Dimitri Papadopoulos Orfanos, Luise Poustka, Juliane H. Fröhner, Robert Whelan, Gunter Schumann, Margaret L. Westwater, Christian Grillon, Hugo Cogo-Moreira, Argyris Stringaris, Monique Ernst
Journal: American Journal of Psychiatry (2022)

Research in adolescent depression has found aberrant intrinsic functional connectivity (iFC) among the ventral striatum (VS) and several brain regions implicated in reward processing. The present study probes this question by taking advantage of the availability of data from a large youth cohort, the IMAGEN Consortium.
Suicide Attempt and Risk of Substance Use Disorders Among Female Youths
Authors: Nathalie Auger, Nicholas Chadi, Aimina Ayoub, Émilie Brousseau, Nancy Low
Journal: JAMA Psychiatry (2022)

Suicide attempts are prevalent among female youths, yet little is known about the subsequent development of substance use disorders.To assess the association between suicide attempts among females before 20 years of age and future risk of substance use disorders.In this longitudinal cohort study, females aged 8 to 19 years (hereafter referred to as youths) who attempted suicide were matched with female youths with no attempt between April 1, 1989, and March 31, 2019, in Quebec, Canada. The cohort was followed up for 31 years, for a total of 2 409 396 person-years, to identify subsequent substance use disorders.Confirmed suicide attempts among females 8 to 19 years of age.The main outcome measure was hospitalization for a substance use disorder later in life. Hazard ratios (HRs) and 95% CIs for the association of suicide attempt with substance use disorders were estimated using Cox proportional hazards regression models adjusted for baseline age, mental illness, resource-limited socioeconomic status, and year at start of follow-up.Among 122 234 female youths (mean [SD] age, 15.6 [1.9] years), 5840 (4.8%) attempted suicide and 4341 (3.6%) developed a substance use disorder. Compared with the 116 394 matched female youths who did not attempt suicide (95.2%), those who attempted suicide had a greater risk of hospitalization for any substance use disorder during the follow-up period (HR, 6.03; 95% CI, 5.39-6.77), especially sedative or hypnotic use disorders (HR, 32.24; 95% CI, 23.29-44.64). Suicide attempt was associated with the development of sedative or hypnotic use disorders up to 5 years (HR, 66.69; 95% CI, 34.72-128.09), although risks remained elevated up to 3 decades later for all substances. Compared with those without suicide attempt, female youths with 3 or more suicide attempts had 21.20 (95% CI, 13.53-32.90) times the risk of substance use disorders, whereas female youths with 1 attempt had 5.70 (95% CI, 5.08-6.41) times the risk of these disorders.In this cohort study, female youths who attempted suicide had increased risk of subsequent substance use disorders compared with female youths who did not attempt suicide. These findings suggest that closer management and prevention of substance use among female youths who attempt suicide may be beneficial.
A<sub>2B</sub>adenosine receptor antagonists rescue lymphocyte activity in adenosine-producing patient-derived cancer models
Authors: Apple Hui Min Tay, Rubén Prieto-Díaz, Shiyong Neo, Le Tong, Xinsong Chen, Valentina Carannante, Björn Önfelt, Johan Hartman, Felix Haglund, Maria Majellaro, Jhonny Azuaje, Xerardo Garcia-Mera, Jose M Brea, Maria I Loza, Willem Jespers, Hugo Gutierrez-de-Teran, Eddy Sotelo, Andreas Lundqvist
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Adenosine is a metabolite that suppresses antitumor immune response of T and NK cells via extracellular binding to the two subtypes of adenosine-2 receptors, A 2 ARs. While blockade of the A 2A ARs subtype effectively rescues lymphocyte activity, with four A 2A AR antagonists currently in anticancer clinical trials, less is known for the therapeutic potential of the other A 2B AR blockade within cancer immunotherapy. Recent studies suggest the formation of A 2A AR/A 2B AR dimers in tissues that coexpress the two receptor subtypes, where the A 2B AR plays a dominant role, suggesting it as a promising target for cancer immunotherapy. Methods We report the synthesis and functional evaluation of five potent A 2B AR antagonists and a dual A 2A AR/A 2B AR antagonist. The compounds were designed using previous pharmacological data assisted by modeling studies. Synthesis was developed using multicomponent approaches. Flow cytometry was used to evaluate the phenotype of T and NK cells on A 2B AR antagonist treatment. Functional activity of T and NK cells was tested in patient-derived tumor spheroid models. Results We provide data for six novel small molecules: five A 2B AR selective antagonists and a dual A 2A AR/A 2B AR antagonist. The growth of patient-derived breast cancer spheroids is prevented when treated with A 2B AR antagonists. To elucidate if this depends on increased lymphocyte activity, immune cells proliferation, and cytokine production, lymphocyte infiltration was evaluated and compared with the potent A 2A AR antagonist AZD-4635. We find that A 2B AR antagonists rescue T and NK cell proliferation, IFNγ and perforin production, and increase tumor infiltrating lymphocytes infiltration into tumor spheroids without altering the expression of adhesion molecules. Conclusions Our results demonstrate that A 2B AR is a promising target in immunotherapy, identifying ISAM-R56A as the most potent candidate for A 2B AR blockade. Inhibition of A 2B AR signaling restores T cell function and proliferation. Furthermore, A 2B AR and dual A 2A AR/A 2B AR antagonists showed similar or better results than A 2A AR antagonist AZD-4635 reinforcing the idea of dominant role of the A 2B AR in the regulation of the immune system.
Catching Up on REMs
Authors: Christian R. Burgess, Thomas E. Scammell
Journal: New England Journal of Medicine (2022)

A recent study of mouse models implicates dopaminergic nerve terminals in the amygdala in releasing the brakes on rapid-eye-movement sleep and on cataplexy in a mouse model of narcolepsy. REM sleep is believed to have a role in processing emotional memories and is under investigation in persons with post-traumatic stress disorder.
Biodistribution, pharmacokinetics and excretion studies of intravenously injected nanoparticles and extracellular vesicles: Possibilities and challenges
Authors: Tore Skotland, Tore Geir Iversen, Alicia Llorente, Kirsten Sandvig
Journal: Advanced Drug Delivery Reviews (2022)

There is a large interest in developing nanoparticles and extracellular vesicles for delivery of therapeutics or imaging agents. Regulatory approval of such products requires knowledge about their biodistribution, metabolism and excretion. We here discuss possibilities and challenges of methods used for such studies, which most often are performed after labelling with radioactive isotopes or fluorescent molecules. It is important to evaluate if the labelled and unlabeled products can be expected to behave similarly in the body. Furthermore, one needs to critically consider whether the labels are still associated with the product at the time of analyses. We discuss advantages and disadvantages of different imaging modalities such as PET, SPECT, MRI, CT, ultrasound and optical imaging for whole-body biodistribution, and describe how to estimate the amount of labelled product in harvested organs and tissue. Microscopy of cells and tissues and various mass spectrometry methods are also discussed in this review.
Role of IL-17 family cytokines in the progression of IPF from inflammation to fibrosis
Authors: Yun-Juan Nie, Shuo-Hua Wu, Ying-Hua Xuan, Gen Yan
Journal: Military Medical Research (2022)

Idiopathic pulmonary fibrosis (IPF) is a fatal chronic interstitial lung disease with no established treatment and is characterized by progressive scarring of the lung tissue and an irreversible decline in lung function. Chronic inflammation has been demonstrated to be the pathological basis of fibrosis. Emerging studies have revealed that most interleukin-17 (IL-17) isoforms are essential for the mediation of acute and chronic inflammation via innate and adaptive immunity. Overexpression or aberrant expression of IL-17 cytokines contributes to various pathological outcomes, including the initiation and exacerbation of IPF. Here, we aim to provide an overview of IL-17 family members in the pathogenesis of IPF.
Persistence of Chemotherapy-Induced Peripheral Neuropathy Despite Vincristine Reduction in Childhood B-Acute Lymphoblastic Leukemia
Authors: Rozalyn L Rodwin, John A Kairalla, Emily Hibbitts, Meenakshi Devidas, Moira K Whitley, Caroline E Mohrmann, Reuven J Schore, Elizabeth Raetz, Naomi J Winick, Stephen P Hunger, Mignon L Loh, Marilyn J Hockenberry, Anne L Angiolillo, Kirsten K Ness, Nina S Kadan-Lottick
Journal: JNCI Journal of the National Cancer Institute (2022)

Children with B-acute lymphoblastic leukemia (B-ALL) are at risk for chemotherapy-induced peripheral neuropathy (CIPN). Children's Oncology Group AALL0932 randomized reduction in vincristine and dexamethasone (every 4 weeks vs 12 weeks during maintenance in the average-risk subset of National Cancer Institute standard-B-ALL (SR AR B-ALL). We longitudinally measured CIPN, overall and by treatment group.AALL0932 standard-B-ALL patients aged 3 years and older were evaluated at T1-T4 (end consolidation, maintenance month 1, maintenance month 18, 12 months posttherapy). Physical and occupational therapists (PT/OT) measured motor CIPN (hand and ankle strength, dorsiflexion and plantarflexion range of motion), sensory CIPN (finger and toe vibration and touch), function (dexterity [Purdue Pegboard], and walking efficiency [Six-Minute Walk]). Proxy-reported function (Pediatric Outcome Data Collection Instrument) and quality of life (Pediatric Quality of Life Inventory) were assessed. Age- and sex-matched z scores and proportion impaired were measured longitudinally and compared between groups.Consent and data were obtained from 150 participants (mean age = 5.1 years [SD = 1.7], 48.7% female). Among participants with completed evaluations, 81.8% had CIPN at T1 (74.5% motor, 34.1% sensory). When examining severity of PT/OT outcomes, only handgrip strength (P < .001) and walking efficiency (P = .02) improved from T1-T4, and only dorsiflexion range of motion (46.7% vs 14.7%; P = .008) and handgrip strength (22.2% vs 37.1%; P = .03) differed in vincristine and dexamethasone every 4 weeks vs vincristine and dexamethasone 12 weeks at T4. Proxy-reported outcomes improved from T1 to T4 (P < .001), and most did not differ between groups.CIPN is prevalent early in B-ALL therapy and persists at least 12 months posttherapy. Most outcomes did not differ between treatment groups despite reduction in vincristine frequency. Children with B-ALL should be monitored for CIPN, even with reduced vincristine frequency.
Modeling transmission of SARS-CoV-2 Omicron in China
Authors: Jun Cai, Xiaowei Deng, Juan Yang, Kaiyuan Sun, Hengcong Liu, Zhiyuan Chen, Cheng Peng, Xinhua Chen, Qianhui Wu, Junyi Zou, Ruijia Sun, Wen Zheng, Zeyao Zhao, Wanying Lu, Yuxia Liang, Xiaoyu Zhou, Marco Ajelli, Hongjie Yu
Journal: Nature Medicine (2022)

Having adopted a dynamic zero-COVID strategy to respond to SARS-CoV-2 variants with higher transmissibility since August 2021, China is now considering whether, and for how long, this policy can remain in place. The debate has thus shifted towards the identification of mitigation strategies for minimizing disruption to the healthcare system in the case of a nationwide epidemic. To this aim, we developed an age-structured stochastic compartmental susceptible-latent-infectious-removed-susceptible model of SARS-CoV-2 transmission calibrated on the initial growth phase for the 2022 Omicron outbreak in Shanghai, to project COVID-19 burden (that is, number of cases, patients requiring hospitalization and intensive care, and deaths) under hypothetical mitigation scenarios. The model also considers age-specific vaccine coverage data, vaccine efficacy against different clinical endpoints, waning of immunity, different antiviral therapies and nonpharmaceutical interventions. We find that the level of immunity induced by the March 2022 vaccination campaign would be insufficient to prevent an Omicron wave that would result in exceeding critical care capacity with a projected intensive care unit peak demand of 15.6 times the existing capacity and causing approximately 1.55 million deaths. However, we also estimate that protecting vulnerable individuals by ensuring accessibility to vaccines and antiviral therapies, and maintaining implementation of nonpharmaceutical interventions could be sufficient to prevent overwhelming the healthcare system, suggesting that these factors should be points of emphasis in future mitigation policies.
Abstract IA003: Darwinian and non-Darwinian evolution of cancer drug resistance
Authors: Marco Gerlinger
Journal: Cancer Research (2022)

Abstract Many highly effective cancer drugs are available for the treatment of solid tumors but resistance almost invariably develops. The ability of cancers to acquire drug resistance by Darwinian evolution is widely accepted. Recently, cellular and microenvironmental plasticity were discovered as additional processes that can lead to drug resistance. I will discuss drug resistance evolution in colorectal cancer and show the need for a comprehensive framework that integrates Darwinian and non-Darwinian evolution in order to understand and address drug resistance evolution. Citation Format: Marco Gerlinger. Darwinian and non-Darwinian evolution of cancer drug resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA003.
Pediatric T-ALL type-1 and type-2 relapses develop along distinct pathways of clonal evolution
Authors: Paulina Richter-Pechańska, Joachim B. Kunz, Tobias Rausch, Büşra Erarslan-Uysal, Beat Bornhauser, Viktoras Frismantas, Yassen Assenov, Martin Zimmermann, Margit Happich, Caroline von Knebel-Doeberitz, Nils von Neuhoff, Rolf Köhler, Martin Stanulla, Martin Schrappe, Gunnar Cario, Gabriele Escherich, Renate Kirschner-Schwabe, Cornelia Eckert, Smadar Avigad, Stefan M. Pfister, Martina U. Muckenthaler, Jean-Pierre Bourquin, Jan O. Korbel, Andreas E. Kulozik
Journal: Leukemia (2022)

Abstract The mechanisms underlying T-ALL relapse remain essentially unknown. Multilevel-omics in 38 matched pairs of initial and relapsed T-ALL revealed 18 (47%) type-1 (defined by being derived from the major ancestral clone) and 20 (53%) type-2 relapses (derived from a minor ancestral clone). In both types of relapse, we observed known and novel drivers of multidrug resistance including MDR1 and MVP , NT5C2 and JAK-STAT activators. Patients with type-1 relapses were specifically characterized by IL7R upregulation. In remarkable contrast, type-2 relapses demonstrated (1) enrichment of constitutional cancer predisposition gene mutations, (2) divergent genetic and epigenetic remodeling, and (3) enrichment of somatic hypermutator phenotypes, related to BLM, BUB1B / PMS2 and TP53 mutations. T-ALLs that later progressed to type-2 relapses exhibited a complex subclonal architecture, unexpectedly, already at the time of initial diagnosis. Deconvolution analysis of ATAC-Seq profiles showed that T-ALLs later developing into type-1 relapses resembled a predominant immature thymic T-cell population, whereas T-ALLs developing into type-2 relapses resembled a mixture of normal T-cell precursors. In sum, our analyses revealed fundamentally different mechanisms driving either type-1 or type-2 T-ALL relapse and indicate that differential capacities of disease evolution are already inherent to the molecular setup of the initial leukemia.
Prevalence of Neuropsychiatric Symptoms and Stroke in Patients with Hereditary Thrombotic Thrombocytopenic Purpura
Authors: Azra Borogovac, Erika Tarasco, Johanna A. Kremer Hovinga, Kenneth D. Friedman, Adam S. Asch, Sara K. Vesely, Calin I. Prodan, Deirdra R. Terrell, James N. George
Journal: Blood (2022)
The unfulfilled potential of mucosal immunization
Authors: James R Baker, Mohammad Farazuddin, Pamela T Wong, Jessica J O'Konek
Journal: Journal of Allergy and Clinical Immunology (2022)

Recent events involving the global coronavirus pandemic have focused attention on vaccination strategies. Although tremendous advances have been made in subcutaneous and intramuscular vaccines during this time, one area that has lagged in implementation is mucosal immunization. Mucosal immunization provides several potential advantages over subcutaneous and intramuscular routes, including protection from localized infection at the site of entry, clearance of organisms on mucosal surfaces, induction of long-term immunity through establishment of central and tissue-resident memory cells, and the ability to shape regulatory responses. Despite these advantages, significant barriers remain to achieving effective mucosal immunization. The epithelium itself provides many obstacles to immunization, and the activation of immune recognition and effector pathways that leads to mucosal immunity has been difficult to achieve. This review will highlight the potential advantages of mucosal immunity, define the barriers to mucosal immunization, examine the immune mechanisms that need to be activated on mucosal surfaces, and finally address recent developments in methods for mucosal vaccination that have shown promise in generating immunity on mucosal surfaces in human trials.